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However, the underlying mechanisms remain unclear. We have previously reported that hepatocyte death locally induces phenotypic changes in the macrophages surrounding the corpse and remnant lipids, thereby promoting liver fibrosis in a murine model of NASH. Here, we demonstrated that lysosomal cholesterol overload triggers lysosomal dysfunction and profibrotic activation of macrophages during the development of NASH. \u03b2-cyclodextrin polyrotaxane (\u03b2CD-PRX), a unique supramolecule, is designed to elicit free cholesterol from lysosomes. Treatment with \u03b2CD-PRX ameliorated cholesterol accumulation and profibrotic activation of macrophages surrounding dead hepatocytes with cholesterol crystals, thereby suppressing liver fibrosis in a NASH model, without affecting the hepatic cholesterol levels. In vitro experiments revealed that cholesterol-induced lysosomal stress triggered profibrotic activation in macrophages predisposed to the steatotic microenvironment. This study provides evidence that dysregulated cholesterol metabolism in macrophages would be a novel mechanism of NASH.<\/jats:p>","DOI":"10.1084\/jem.20220681","type":"journal-article","created":{"date-parts":[[2023,7,21]],"date-time":"2023-07-21T02:21:11Z","timestamp":1689906071000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":52,"title":["Lysosomal cholesterol overload in macrophages promotes liver fibrosis in a mouse model of NASH"],"prefix":"10.1084","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2573-2182","authenticated-orcid":true,"given":"Michiko","family":"Itoh","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04chrp450","id-type":"ROR","asserted-by":"publisher"}],"name":"Research Institute of Environmental Medicine, Nagoya University 1 Department of Molecular Medicine and Metabolism, , Nagoya, 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